bims-hypusi 2024-01-28 papers

Issue of 2024–01–28
two papers selected by
Sebastian J. Hofer, University of Graz

Am J Respir Crit Care Med. 2024 Jan 23.

Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Sarah-Eve Lemay, Yann Grobs, Charlotte Romanet, Sandra Martineau, Mabrouka Salem, Tsukasa Shimauchi, Sandra Breuils-Bonnet, Alice Bourgeois, Charlie Théberge, Andréanne Pelletier, François Potus, Steeve Provencher, Sébastien Bonnet, Olivier Boucherat.

RATIONALE: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a post-translational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) due to excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis.
OBJECTIVES: To characterize the role of hypusine signaling in PAH.
METHODS: Molecular, genetic, and pharmacological approaches were used both in vitro and in vivo to investigate the role of hypusine signaling in pulmonary vascular remodeling.
MEASUREMENTS AND MAIN RESULTS: Hypusine forming enzymes (deoxyhypusine synthase, DHPS and deoxyhypusine hydroxylase, DOHH) and hypusinated eIF5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro, inhibition of DHPS using GC7 or short hairpin RNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo, inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice and that its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. Using mass spectrometry, we show that hypusine signaling promotes the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation.
CONCLUSIONS: These findings support inhibiting hypusine signaling as a potential treatment for PAH.

Keywords: DHPS; hypusine; right ventricular failure; smooth muscle cells; spermidine

DOI: https://doi.org/10.1164/rccm.202305-0909OC

Vaccines (Basel). 2024 Jan 19. pii: 101. [Epub ahead of print]12(1):

Toxoplasma gondii eIF-5A Modulates the Immune Response of Murine Macrophages In Vitro.

Xinchao Liu, Xiaoyu Li, Chunjing Li, Mingmin Lu, Lixin Xu, Ruofeng Yan, Xiaokai Song, Xiangrui Li.

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan that can elicit a robust immune response during infection. Macrophage cells have been shown to play an important role in the immune response against T. gondii. In our previous study, the eukaryotic translation initiation factor 5A (eIF-5A) gene of T. gondii was found to influence the invasion and replication of tachyzoites. In this study, the recombinant protein of T. gondii eIF-5A (rTgeIF-5A) was incubated with murine macrophages, and the regulatory effect of TgeIF-5A on macrophages was characterized. Immunofluorescence assay showed that TgeIF-5A was able to bind to macrophages and partially be internalized. The Toll-like receptor 4 (TLR4) level and chemotaxis of macrophages stimulated with TgeIF-5A were reduced. However, the phagocytosis and apoptosis of macrophages were amplified by TgeIF-5A. Meanwhile, the cell viability experiment indicated that TgeIF-5A can promote the viability of macrophages, and in the secretion assays, TgeIF-5A can induce the secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO) from macrophages. These findings demonstrate that eIF-5A of T. gondii can modulate the immune response of murine macrophages in vitro, which may provide a reference for further research on developing T. gondii vaccines.

Keywords: Toxoplasma gondii; eukaryotic translation initiation factor 5A; immune response; in vitro; macrophages

DOI: https://doi.org/10.3390/vaccines12010101